A large body of evidence indicates that impaired energy homeostasis has a causative role in motor neuron death in amyotrophic lateral sclerosis (ALS). Recently we have found that human G93A human superoxide dismutase (SOD1) mutant transgenic male mice administered prophylactically with a high caloric ketogenic diet have an overall significant slower decline in ALS type motor impairment and lower mortality rate compared to SOD1-G93A mice fed a standard laboratory diet. Coincidentally we found a significant increase in levels of ketone bodies and notably D-3-beta-hydroxybutyrate (D-beta-HB) in the blood of transgenic ALS mice fed the ketogenic diet. We hypothesize that the protective effect of the ketogenic diet is due to increased utilization of ketone bodies in mitochondrial metabolism which is defective in SOD1-G93A mice. We propose 1) to determine the effects of D-beta-HB as a supplement, on motor function, muscle strength and survival in SOD1-G93A mice, and 2) to demonstrate that a mechanism of action of D-beta-HB is alleviating the blockage of mitochondrial function and consequent glutamate excitotoxicity associated with SOD1-G93A ALS type neuropathology. While the studies proposed in Aim 1, will provide immediate preclinical evidence on the beneficial role of D-beta-HB in ALS-type motor impairment in SOD1-G93A mutant mice, the studies proposed in Aims 2-3 will clarify the molecular and cellular mechanism(s) involved in D-beta-HB- mediated neuroprotection underlying ALS-type neurological improvement in vivo. Collectively, the proposed studies will provide impetus for larger preclinical studies testing the neuroprotective role of D-beta-HB in ALS-type neurodegeneration and will provide precious information about the possibility of developing the application of D-beta-HB as a potential novel alternative therapeutic agent in ALS. The studies proposed in this application will provide immediate preclinical evidence on the beneficial role of ketogenic diet and keton bodies, notably D-3-beta-hydroxybutyrate (D-beta-HB) in amyotrophic lateral sclerosis (ALS)- type motor impairment in SOD1-G93A mutant mice. Moreover, the studies will clarify the molecular and cellular mechanism(s) involved in ketones mediated neuroprotection underlying ALS-type neurological improvement in vivo. Collectively, the proposed studies will provide impetus for larger preclinical studies testing the neuroprotective role of D-beta-HB in ALS-type neurodegeneration and will provide precious information about the possibility of developing the application of D-beta-HB as a potential novel alternative therapeutic agent in ALS. [unreadable] [unreadable] [unreadable]